Thioquinolone compounds which have useful pharmaceutical activity

ABSTRACT

Disclosed is a thioquinolone derivative which exhibits highly selective antibacterial activity against Helicobacter pylori.

This is a 371 application of PCT/JP95102052 filed on Oct. 6, 1995.

TECHNICAL FIELD

The present invention relates to novel thioquinolone derivativesrepresented by the formula I and having antibacterial activity againstHelicobacter pylori or pharmaceutically acceptable salts thereof andantibacterial agents containing the derivatives as effective components:##STR1## wherein R₁ and R₂ respectively represent hydrogen atom or R₁and R₂ are joined to form --O--(CH₂)₂ --;

R₃ represents halogen atom, C₁ -C₁₂ alkyl group, C₁ -C₁₂ alkoxy group,lower alkylsulfonyloxy group, carboxy lower alkoxy group, loweralkylthio group, benzyloxy group, benzylthio group, phenoxy group,styryl group, nitro group, phenyl group, naphthyl group, piperazinylgroup, morpholino group or hydroxyl group or represents --CH₂ R₅, --COR₆or --NR₇ R₈ wherein R₅ represents benzyl group, phenyl group, hydroxylgroup, lower alkoxy group, lower alkylcarbonyloxy group, phenoxy group,di-lower alkylamino group or benzimidazolylthio group, R₆ representslower alkyl group or amino group and R₇ and R₈ respectively representlower alkyl group; and

R₄ represents hydrogen atom or lower alkyl group or is coupled with R₃to form cyclohexene ring, benzene ring or pyridine ring,

R₃ being not halogen atom at any of positions 5 to 8, methyl group atposition 6 or methoxy group at position 6 of the quinoline ring when R₁,R₂ and R₄ are respectively hydrogen atom,

R₃ and R₄ being not at positions 6 and 7 or positions 6 and 8 of thequinoline ring when R₁ and R₂ are respectively hydrogen atom and R₄ islower alkyl group.

BACKGROUND ART

Helicobacter pylori is a spiral, short rod-shaped, gram-negativebacterium having at its one pole several sheath flagella. The bacteriaare detected both in the gastric mucous layer and on the surface ofgastric epithelial cells.

The fact that spiral bacteria live on and in a gastric mucosa has beenobserved by many researchers. Firstly in 1983, Marshall et al. succeededin cultivating spiral bacteria through isolation of the same from agastric mucosa. The bacterium was originally named Campylobacter pylorisince its shapes and biochemical characteristics are analogous to thoseof the genus Campylobacter which is one of known enteritis-causingbacterial genera. However, later bacterial taxonomic researchesestablished a new independent genus including the bacterium, and thebacterium was renamed Helicobacter pylori.

In 1984, Marshall et al. detected the bacteria at high percentage frompatients suffering from peptic ulcer such as gastric and duodenal ulcersand chronic gastritis, and suggested relevance of the bacteria tooccurrence and reccurrence of these diseases. As conventional remediesagainst peptic ulcer, medical treatments with gastric secretioninhibitors have been utilized; advent of H₂ -blocker such as cimetidineand proton-pump inhibitor such as omeprazole enhanced the cure rate upto 80-90%. However, it has been reported that about 50% of patientshealed with administration of anti-ulcer agents have relapse orreccurrence of ulcers within twelve months and that, particularly,patients healed with gastric secretion inhibitors such as H₂ -blockersand proton-pump inhibitors have relapse rate of as high as 70-90%. Thus,prevention of the relapse or reccurrence is one of greatest problems inthe treatment.

There have, however, been recently increasingly reported that removal ofHelicobacter pylori (hereinafter referred to as Hp) with anantibacterial agent will decrease ulcer relapse rate see for exampleSAISHIN-IGAKU: Vol. 44, No. 2, pp. 295-302, (1989)!; and, in February1994, NIH in U.S.A. advised necessity of eradicating Hp in the treatmentof peptic ulcer. Hp-removing agents used nowadays are for exampleantibiotics and bismuth preparations. Antibiotics are not suitable forlong-term use since they may also affect other intestinal bacteria andmay cause advent of resistant bacteria. Treatment with bismuthpreparations is rather problematic since the bismuth preparations areweak in antibacterial activity and may cause vomiting, diarrhea and/orside effects on central nervous system.

Anti-ulcer agents with antibacterial activities against Hp have beenproposed for example in Japanese Patent Provisional Publication (Kokai)No. 4-364160 (European Patent Provisional Publication No. 470006) andJapanese Patent Provisional Publication (Kokai) No. 5-117268; however,none of the proposed agents have sufficient selectivity andantibacterial activity. Under such circumstances, there have been demandon development of preparations having higher selectivity on Hp as wellas antibacterial activity against Hp in the treatment of peptic ulcerand chronic gastritis with Hp infection.

In order to overcome the above-mentioned problems, we, the inventorscarried out intensive studies to find that a thioquinolone derivative ofthe formula I has excellent selective antibacterial activity against Hp,thus accomplishing the present invention.

Conventionally proposed thioquinolone derivatives are for use assynthetic intermediates in agricultural and horticultural bactericides,cardiotonic agents or the like see Japanese Patent ProvisionalPublication (Kokai) No. 6-41117 and U.S. Pat. No. 5,081,121!. Thepresent invention is a first proposal on thioquinolone derivatives asantibacterial agents against Hp.

DISCLOSURE OF THE INVENTION

The terms used for definition of letters in the formula I by which thecompounds of the present invention are represented are defined andexemplified in the following.

The wording "lower" refers to a group having 1 to 6 carbon atoms unlessotherwise indicated.

The "lower alkyl group" refers to a straight- or branched-chain alkylgroup such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,n-pentyl, n-hexyl or the like.

The "lower alkoxy group" refers to a straight- or branched-chain alkoxygroup such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, n-pentyloxy, n-hexyloxy or the like.

The wording "C₁ -C₁₂ " refers to a group having 1 to 12 carbon atoms.

The "C₁ -C₁₂ alkyl group" refers to a straight- or branched-chain alkylgroup such as heptyl, octyl, nonyl, decyl, undecyl, dodecyl in additionto the above-mentioned groups as "lower alkyl group".

The "C₁ -C₁₂ alkoxy group" refers to a straight- or branched-chainalkoxy group such as heptyloxy, octyloxy, nonyloxy, decyloxy,undecyloxy, dodecyloxy in addition to the above-mentioned groups as"lower alkoxy group".

The "halogen atom" may be fluorine, chlorine, bromine or iodine atom.

The compounds according to the present invention may be as follows,though the present invention is not limited to these compounds.

5-Methylquinoline-4(1H)-thione

7-Methylquinoline-4(1H)-thione

8-Methylquinoline-4(1H)-thione

8-Isopropylquinoline-4(1H)-thione

7,8-Dimethylquinoline-4(1H)-thione

7-Isopropylquinoline-4(1H)-thione

7-n-Hexylquinoline-4(1H)-thione

7-Dodecylquinoline-4(1H)-thione

7-Hydroxymethylquinoline-4(1H)-thione

7-Methoxymethylquinoline-4(1H)-thione

7-Phenoxymethylquinoline-4(1H)-thione

7-Acetoxymethylquinoline-4(1H)-thione

7-Styrylquinoline-4(1H)-thione

7-Benzylquinoline-4(1H)-thione

7-Phenethylquinoline-4(1H)-thione

7-N,N-Dimethylaminomethylquinoline-4(1H)-thione

7-(2-Benzimidazolyl)thiomethylquinoline-4(1H)-thione

7-Phenylquinoline-4(1H)-thione

7-(2-Naphtyl)quinoline-4(1H)-thione

7-Hydroxyquinoline-4(1H)-thione

7-Methoxyquinoline-4(1H)-thione

8-Methoxyquinoline-4(1H)-thione

7-Ethoxyquinoline-4(1H)-thione

7-n-Propoxyquinoline-4(1H)-thione

7-Isopropoxyquinoline-4(1H)-thione

8-Isopropoxyquinoline-4(1H)-thione

7-tert-Butoxyquinoline-4(1H)-thione

7-n-Hexyloxyquinoline-4(1H)-thione

7-Octyloxyquinoline-4(1H)-thione

7-Dodecyloxyquinoline-4(1H)-thione

7-Benzyloxyquinoline-4(1H)-thione

7-Phenoxyquinoline-4(1H)-thione

7-(5-Carboxy-n-pentyloxy)quinoline-4(1H)-thione

7-Methanesulfonyloxyquinoline-4(1H)-thione

7-Methylthioquinoline-4(1H)-thione

7-Isopropylthioquinoline-4(1H)-thione

7-n-Butylthioquinoline-4(1H)-thione

7-Benzylthioquinoline-4(1H)-thione

7-Acetylquinoline-4(1H)-thione

7-Carbamoylquinoline-4(1H)-thione

7-N,N-Dimethylaminoquinoline-4(1H)-thione

7-N,N-Diethylaminoquinoline-4(1H)-thione

8-N,N-Dimethylaminoquinoline-4(1H)-thione

7-(N-Isopropyl-N-methylamino)quinoline-4(1H)-thione

7-(1-Piperazinyl)quinoline-4(1H)-thione

7-Morpholinoquinoline-4(1H)-thione

7-Nitroquinoline-4(1H)-thione

8-Nitroquinoline-4(1H)-thione

7-Chloro-2,3-dihydrofuro 2,3-b!quinoline-4(1H)-thione

7-Chloro-8-methylquinoline-4(1H)-thione

7-Isopropyl-8-chloroquinoline-4(1H)-thione

7-N,N-Dimethylamino-8-ethylquinoline-4(1H)-thione

7-Methyl-8-methoxyquinoline-4(1H)-thione

5-Nitro-8-methylquinoline-4(1H)-thione

7-Isopropyl-8-N,N-dimethylaminoquinoline-4(1H)-thione

Benzo h!quinoline-4(1H)-thione

7,8,9,10-Tetrahydrobenzo h!quinoline-4(1H)-thione

1,7-Phenanthroline-4(1H)-thione

1,10-Phenanthroline-4(1H)-thione

The compounds of the present invention may exist in the form oftautomers as shown below. It is, therefore, to be understood that any ofsuch tautomers are included in the category of the compounds of theformula I. ##STR2## wherein R₁, R₂, R₃ and R₄ are as defined above.

Furthermore, according to substituents and the like, the compounds ofthe present invention may be in the form of pharmaceutically acceptablesalts such as alkali salts, organic ammonium salts or acid additionsalts. The appropriate alkali salts which can be used include, forexample, potassium salt, sodium salt, calcium salt, magnesium salt andbarium salt. The appropriate organic ammonium salts which can be usedinclude, for example, ethyl ammonium salt and trimethyl ammonium salt.And, the appropriate acid addition salts which can be used includeinorganic salts such as hydrochloride, sulfate, hydrobromide, nitrateand phosphate as well as organic acid salts such as acetate, oxalate,propionate, glycolate, lactate, pyruvate, malonate, succinate, maleate,fumarate, malate, tartarate, citrate, benzoate, cinnamate,methanesulfonate, benzenesulfonate, p-toluenesulfonate salicylate.

The compounds of the present invention may be prepared by the followingprocedure of conversion of 4-hydroxyquinoline derivative (formula II) or4-haloquinoline derivative (formula III) to thione at the position 4 ofthe quinoline ring as shown in the following reaction scheme 1 or 2. (1)In conversion of 4-hydroxyquinoline derivative of the formula II tothione, a mole of compound of the formula II in a solvent such aspyridine, toluene or xylene is reacted with a mole or more of phosphoruspentasulfide, silicon disulfide or Lawesson's reagent for 0.5-5 hoursunder reflux to obtain the compound of the present invention. ##STR3##wherein R₁, R₂, R₃ and R₄ are as defined above. (2) In conversion of4-haloquinoline derivative of the formula III to thione, a mole ofcompound of the formula III in a solvent such as methanol, ethanol,n-propanol is reacted with a mole or more of sodium hydrosulfide,potassium hydrosulfide or thiourea at room temperature for 8 hours to 8days or at 60°-100° C. for 0.5-48 hours to obtain the compound of thepresent invention. ##STR4## wherein R₁, R₂, R₃ and R₄ are as definedabove and X represents halogen atom.

The compounds of the present invention thus obtained may be separatedand purified by a usual manner such as extraction, condensation,neutralization, filtration, recrystallization or column chromatography,if necessary.

The pharmaceutically acceptable salts of the compounds of the presentinvention may be prepared by various known methods in the art.

The compounds of the formulas II and III which are the startingmaterials in the above-mentioned processes can be readily synthesizedaccording to a process described for example in Org. Syn. Coll. Vol. 3,p. 272 or Japanese Patent Publication (Kokoku) No. 47-43952.

Next, described is antibacterial activity of the compound of the presentinvention represented by the formula I. The numbers of test compounds inAntibacterial Tests 1 and 2 correspond to those in Examples referred tohereinafter. Controls used were antibiotic (amoxicillin) and anti-ulceragent (lansoprazole) having antibacterial activity against Hp.

Antibacterial test 1

Antibacterial test against Hp was performed in substantial accordancewith agar plate dilution method (anaerobic MIC method) based on Standardmethod of The Japan Society of Chemotherapy to determine minimuminhibitory concentration (MIC) of the respective test compounds.

Preparation of medium for sensitivity testing!

The respective test compounds were sequentially dissolved in dimethylsulfoxide (DMSO) and serially diluted twofold. These diluted solutionsof the compounds are respectively added to brucella agar medium(prepared by Difco) containing 7% horse blood free from fibrin (preparedby NIPPON BIOTEST KENKYUSHO) to prepare agar plates for determinationwith concentration of 0.05-100 μg/ml.

Preparation of inocula!

Strain used for inoculation was Helicobacter pylori standard strain ATCC43526 (NCTC 11916). For pre-culturing of bacteria to be inoculated, theabove-mentioned strain freezingly conserved at -135° C. was thawed in awarm bath (40° C.), applied on a brucella agar medium containing 7%horse blood free from fibrin, and microaerobically cultured in a jar foranaerobic bacteria at 37° C. for 3 days. The solution of bacteria to beinoculated was prepared by collecting colonies grown on the culturemedium and suspending the same in the brucella broth.

The suspension was made such that the concentration of the bacteria tobe inoculated provides adsorbancy O.D_(570nm) =0.50, and 2.0×10⁷ CFU/mlof the solution of the bacteria was prepared, 5 μl of which wasinoculated with multi-inoculator (manufactured by SAKUMA SEISAKUSHO).Culturing was performed for 3 days under the same conditions as those ofthe pre-culturing and the MIC (unit: μg/ml) was determined by observingwhether the bacteria grew or not. The obtained results are shown inTable 1.

                  TABLE 1                                                         ______________________________________                                        test compound  MIC (μg/ml)                                                 ______________________________________                                        compound 1     0.39                                                           compound 2     1.56                                                           compound 3     1.56                                                           compound 6     1.56                                                           compound 7     6.25                                                           compound 11    0.39                                                           compound 12    6.25                                                           compound 13    1.56                                                           compound 15    0.39                                                           compound 16    1.56                                                           compound 17    0.39                                                           compound 19    3.13                                                           compound 22    3.13                                                           compound 23    0.78                                                           compound 24    1.56                                                           compound 25    6.25                                                           compound 26    1.56                                                           compound 28    0.39                                                           compound 29    0.78                                                           compound 30    1.56                                                           compound 31    0.39                                                           compound 32    0.78                                                           compound 33    6.25                                                           compound 34    0.78                                                           compound 36    0.39                                                           compound 37    0.78                                                           compound 38    0.78                                                           compound 39    0.39                                                           compound 40    0.20                                                           compound 41    0.78                                                           compound 42    0.39                                                           compound 45    0.39                                                           compound 46    3.13                                                           compound 47    0.20                                                           compound 48    0.20                                                           compound 49    0.39                                                           compound 50    1.56                                                           compound 51    1.56                                                           compound 52    6.25                                                           compound 53    3.13                                                           compound 54    3.13                                                           compound 55    0.39                                                           amoxicillin    0.05                                                           lansoprazole   12.5                                                           ______________________________________                                    

As is clear from the above table 1, the compounds of the presentinvention exhibit excellent antibacterial activities against Hp.Structurally, the compounds of the formula I wherein R₁, R₂ and R₄ arerespectively hydrogen atom and R₃ is at position 7 or 8 of the quinolinering or wherein R₁ and R₂ are respectively hydrogen atom and R₃ and R₄are at the positions 7 and 8 of the quinoline ring exhibited especiallyexcellent activities.

Antibacterial Test 2

Then, tested were antibacterial activities of the typical compounds ofthe present invention against gram-positive and-negative bacteria otherthan Hp. MICs of the typical compounds of the present invention weredetermined in substantial accordance with agar plate dilution method(aerobic MIC method) based on Standard method of The Japan Society ofChemotherapy.

Preparation of medium for sensitivity testing!

The respective test compound were dissolved in dimethyl sulfoxide (DMSO)and serially diluted twofold. These diluted solutions of the compoundswere respectively added to sensitive-disk agar medium-N (manufactured byNISSUI SEIYAKU) to prepare agar plates for determination withconcentration of 0.05-100 μg/ml.

Preparation of inocula!

Strains used for inoculation were 7 species as shown in Table 2. Thebelow-mentioned strains freezingly conserved at -135° C. were thawed ina warm bath (40° C.), cultured in a sensitivity-determining bouillon at37° C. for 18-20 hours, and then diluted with the above-mentioned mediumto prepare about 1.0×106CFU/ml of bacterial solution.

Inoculation was made by 5 μl by multi-inoculator (manufactured by SAKUMASEISAKUSHO). Culturing was made under the same conditions as those ofthe pre-culturing and the MIC (unit: μg/ml) was determined by observingwhether the bacteria grew or not. The obtained results are shown inTables 2 to 12.

                  TABLE 2                                                         ______________________________________                                                  MIC (μg/ml)                                                      strain      compound 1 Compound 2 compound 3                                  ______________________________________                                        S.aureus FDA 209P                                                                         50         >100       >100                                        M.luteus ATCC 9341                                                                        >100       >100       >100                                        E.faecalis                                                                    RIMD 3336001                                                                              >100       >100       >100                                        B.subtilis PCI 219                                                                        >100       >100       >100                                        E.coli NIHJ JC-2                                                                          >100       >100       >100                                        K.pneumoniae PCI                                                                          >100       >100       >100                                        602                                                                           P.aeruginosa IFO                                                                          >100       >100       >100                                        3445                                                                          ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                                  MIC (μg/ml)                                                      strain      compound 6 compound 15                                                                              compound 16                                 ______________________________________                                        S.aureus FDA 209P                                                                         >100       >100       50                                          M.luteus ATCC 9341                                                                        >100       >100       100                                         E.faecalis  >100       >100       50                                          RIMD 3336001                                                                  B.subtilis PCI 219                                                                        >100       >100       100                                         E.coli NIHJ JC-2                                                                          >100       >100       >100                                        K.pneumoniae PCI                                                                          >100       >100       >100                                        602                                                                           P.aeruginosa IFO                                                                          >100       >100       >100                                        3445                                                                          ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                                  MIC (μg/ml)                                                      strain      compound 17                                                                              compound 22                                                                              compound 23                                 ______________________________________                                        S.aureus FDA 209P                                                                         >100       >100       >100                                        M.luteus ATCC 9341                                                                        >100       >100       >100                                        E.faecalis  >100       >100       >100                                        RIMD 3336001                                                                  B.subtilis PCI 219                                                                        >100       >100       >100                                        E.coli NIHJ JC-2                                                                          >100       >100       >100                                        K.pneumoniae PCI                                                                          >100       >100       >100                                        602                                                                           P.aeruginosa IFO                                                                          >100       >100       >100                                        3445                                                                          ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                                  MIC (μg/ml)                                                      strain      compound 24                                                                              compound 26                                                                              compound 28                                 ______________________________________                                        S.aureus FDA 209P                                                                         >100       100        25                                          M.luteus ATCC 9341                                                                        >100       >100       50                                          E.faecalis  >100       >100       50                                          RIMD 3336001                                                                  B.subtilis PCI 219                                                                        >100       >100       >100                                        E.coli NIHJ JC-2                                                                          >100       >100       >100                                        K.pneumoniae PCI                                                                          >100       >100       >100                                        602                                                                           P.aeruginosa IFO                                                                          >100       >100       >100                                        3445                                                                          ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                                  MIC (μg/ml)                                                      strain      compound 29                                                                              compound 30                                                                              compound 31                                 ______________________________________                                        S.aureus FDA 209P                                                                         25         >100       >100                                        M.luteus ATCC 9341                                                                        50         100        >100                                        E.faecalis  50         >100       >100                                        RIMD 3336001                                                                  B.subtilis PCI 219                                                                        100        >100       >100                                        E.coli NIHJ JC-2                                                                          >100       >100       >100                                        K.pneumoniae PCI                                                                          >100       >100       >100                                        602                                                                           P.aeruginosa IFO                                                                          >100       >100       >100                                        3445                                                                          ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                                  MIC (μg/ml)                                                      strain      compound 32                                                                              compound 34                                                                              compound 36                                 ______________________________________                                        S.aureus FDA 209P                                                                         >100       >100       100                                         M.luteus ATCC 9341                                                                        >100       >100       100                                         E.faecalis  >100       >100       >100                                        RIMD 3336001                                                                  B.subtilis PCI 219                                                                        >100       >100       100                                         E.coli NIHJ JC-2                                                                          >100       >100       >100                                        K.pneumoniae PCI                                                                          >100       >100       >100                                        602                                                                           P.aeruginosa IFO                                                                          >100       >100       >100                                        3445                                                                          ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                                  MIC (μg/ml)                                                      strain      compound 37                                                                              compound 38                                                                              compound 39                                 ______________________________________                                        S.aureus FDA 209P                                                                         >100       >100       >100                                        M.luteus ATCC 9341                                                                        >100       >100       >100                                        E.faecalis  >100       >100       >100                                        RIMD 3336001                                                                  B.subtilis PCI 219                                                                        >100       >100       >100                                        E.coli NIHJ JC-2                                                                          >100       >100       >100                                        K.pneumoniae PCI                                                                          >100       >100       >100                                        602                                                                           P.aeruginosa IFO                                                                          >100       >100       >100                                        3445                                                                          ______________________________________                                    

                  TABLE 9                                                         ______________________________________                                                  MIC (μg/ml)                                                      strain      compound 40                                                                              compound 41                                                                              compound 47                                 ______________________________________                                        S.aureus FDA 209P                                                                         >100       >100       >100                                        M.luteus ATCC 9341                                                                        >100       >100       50                                          E.faecalis  >100       >100       >100                                        RIMD 3336001                                                                  B.subtilis PCI 219                                                                        >100       >100       >100                                        E.coli NIHJ JC-2                                                                          >100       >100       >100                                        K.pneumoniae PCI                                                                          >100       >100       >100                                        602                                                                           P.aeruginosa IFO                                                                          >100       >100       >100                                        3445                                                                          ______________________________________                                    

                  TABLE 10                                                        ______________________________________                                                  MIC (μg/ml)                                                      strain      compound 48                                                                              compound 49                                                                              compound 50                                 ______________________________________                                        S.aureus FDA 209P                                                                         100        >100       >100                                        M.luteus ATCC 9341                                                                        >100       >100       >100                                        E.faecalis  >100       >100       >100                                        RIMD 3336001                                                                  B.subtilis PCI 219                                                                        >100       >100       >100                                        E.coli NIHJ JC-2                                                                          >100       >100       >100                                        K.pneumoniae PCI                                                                          >100       >100       >100                                        602                                                                           P.aeruginosa IFO                                                                          >100       >100       >100                                        3445                                                                          ______________________________________                                    

                  TABLE 11                                                        ______________________________________                                                  MIC (μg/ml)                                                      strain      compound 51                                                                              compound 53                                                                              compound 54                                 ______________________________________                                        S.aureus FDA 209P                                                                         100        >100       100                                         M.luteus ATCC 9341                                                                        >100       >100       >100                                        E.faecalis  100        >100       >100                                        RIMD 3336001                                                                  B.subtilis PCI 219                                                                        >100       >100       >100                                        E.coli NIHJ JC-2                                                                          >100       >100       >100                                        K.pneumoniae PCI                                                                          >100       >100       >100                                        602                                                                           P.aeruginosa IFO                                                                          >100       >100       >100                                        3445                                                                          ______________________________________                                    

                  TABLE 12                                                        ______________________________________                                                  MIC (μg/ml)                                                      strain      compound 55                                                                              amoxicillin                                                                              lansoprazol                                 ______________________________________                                        S.aureus FDA 209P                                                                         >100       0.1        >100                                        M.luteus ATCC 9341                                                                        >100       ≦0.05                                                                             >100                                        E.faecalis  >100       0.2        >100                                        RIMD 3336001                                                                  B.subtilis PCI 219                                                                        >100       0.2        >100                                        E.coli NIHJ JC-2                                                                          >100       3.13       >100                                        K.pneumoniae PCI                                                                          >100       50         >100                                        602                                                                           P.aeruginosa IFO                                                                          >100       >100       >100                                        3445                                                                          ______________________________________                                    

As is clear from the above test results, the typical compounds of thepresent invention hardly exhibit antibacterial activity against theabove-mentioned seven gram-positive or -negative strains. This meansthat the compounds of the present invention has selective antibacterialactivity against Hp.

Thus, the compounds of the present invention have selective andeffective antibacterial activities against the genus Helicobacterrepresented by Hp and have no antibacterial activities againstintestinal bacteria such as E. coli, hardly cause any fluctuation ofintestinal bacterial flora which may be caused in the case of otherantibacterial agents such as penicillin and cephalosporin and are lessdangerous of causing side effects such as enteritis and pseudomembranouscolitis based on microbial substitution. Moreover, the compounds of thepresent invention exhibit the antibacterial activity selectively againstthe genus Helicobacter, so that they are deemed to hardly causeresistance induction for other strains, which is frequently seen in thecase of existing antibacterial agents such as β-lactams and macrolides,as well as cross-resistance with other antibacterial agents.

Therefore, the compounds of the present invention can be applied asselective antibacterial agent against Hp for the treatment andprevention of reccurrence of peptic ulcer and chronic gastritis.

The compounds of the present invention may be administered to humanorally or parenterally. In oral administration, the compounds may be inthe form of tablets, coated tablets, powders, granules, capsules,microcapsules, syrups and the like; and in parenteral administration, inthe form of injections which may include soluble freeze-drying form,suppositories and the like. In the preparation of these forms,pharmaceutically acceptable diluent bases, binders, lubricants,disintegrators, suspensions, emulsifiers, antiseptics, stabilizers anddispersing agents, for example, lactose, sucrose, starch, dextrin,crystalline cellulose, kaolin, calcium carbonate, talc, magnesiumstearate, distilled water and physiological saline solution may be used.

BEST MODE FOR CARRYING OUT THE INVENTION Preparations and Examples!

The present invention is more specifically illustrated with reference tothe following preparations and examples. It is to be, however, notedthat the present invention is not limited to the preparations andexamples.

Preparation 1: Preparation of 4-hydroxy-7-methoxyquinoline (1)m-Anisidine (12.3 g, 0.1 mol) is mixed with diethylethoxymethylenemalonate (21.6g, 0.1 mol) without solvent and stirred at110°-120° C. for an hour with resulting ethanol being removed. Thereactant was dissolved in diphenyl ether (150 ml) and further stirred at230° C. for 4 hours with resulting ethanol being removed. The reactionmixture was allowed to cool to room temperature and was added with ethylacetate (300 ml). The resulting precipitates were collected byfiltration to obtain 12.4 g (50%) of ethyl4-hydroxy-7-methoxy-3-quinolinecarboxylate.

NMR:δ 1.28(3H, t), 3.87(3H, s), 4.20(2H, q), 7.00(2H, m), 8.05(1H, d),8.48(1H, s), 12.09(1H, brs)

(2) Ethyl 4-hydroxy-7-methoxy-3-quinolinecarboxylate (24.7 g, 0.1 mol)was hydrolysed with 2N aqueous solution of sodium hydroxide (250 ml)through boiling for 2 hours. The reaction mixture was allowed to cool toroom temperature and adjusted with 2N hydrochloric acid to pH 5. Theresulting precipitates were collected by filtration and washed withwater. The precipitates were dried at 100°-120° C. for 3 hours in anoven and further dried under reduced pressure overnight over calciumchloride to obtain 21.4 g (98%) of4-hydroxy-7-methoxy-3-quinolinecarboxylic acid.

NMR:δ 3.92(3H, s), 7.19(1H, d), 7.20(1H, dd), 8.19(1H, d), 8.82(1H, s),13.15(1H, brs)

(3) 4-Hydroxy-7-methoxy-3-quinolinecarboxylic acid (21.4 g, 0.1 mol) wasadded with diphenyl ether (150 ml) and decarboxylated at 250° C. for 2hours. The reaction mixture was allowed to cool to room temperature andadded with ethyl acetate (300 ml). The resulting precipitates werecollected by filtration to obtain crude 4-hydroxy-7-methoxyquinoline(15.0 g). This was recrystallized from water (about 300 ml) to obtain14.8 g (86%) of 4-hydroxy-7-methoxyquinoline.

Melting Point: 215°-217° C.; MS m/z: 215 (M⁺); NMR:δ 3.87(3H, s),6.20(1H, d), 6.87(1H, d), 6.91(1H, dd), 7.59(1H, d), 8.23(1H, d),11.30(1H, brs)

Starting from the corresponding substituted aniline, the following4-hydroxyquinoline derivatives are obtained in accordance with theprocedure of the Preparation 1.

4-Hydroxy-7-isopropylquinoline

MS m/z: 187 (M⁺);

4-Hydroxy-7-phenylquinoline

Melting Point: >300° C. (dec.); MS m/z: 221 (M⁺); NMR:δ 6.37(1H, d),7.38-7.52(3H, m), 7.64-7.81(4H, m), 8.04(1H, d), 8.32(1H, d)

4-Hydroxy-7-iodoquinoline

Melting Point: >240° C. (dec.); MS m/z: 187 (M⁺); NMR:δ 6.04(1H, d),7.61(1H, dd), 7.80-7.94(3H, m), 11.71(1H, brs)

4-Hydroxy-7-phenoxymethylquinoline

Melting Point: 183-184° C.; MS m/z: 251 (M⁺); NMR:δ 5.26(2H, s),6.03(1H, d), 6.90-7.05(3H, m), 7.27-7.39(3H, m), 7.59(1H, s), 7.88(1H,d), 8.20(1H, d), 11.75(1H, brs)

7-N,N-Dimethylaminomethyl-4-hydroxyquinoline

MS m/z: 202 (M⁺); NMR(DMSO-d₆)δ: 2.20(6H, s), 3.52(2H, s), 6.00(1H, d),7.24(1H, d), 7.45(1H, s), 7.86(1H, dd), 8.03(1H, d), 11.66(1H, brs)

7-(N-Isopropyl-N-methylamino)-4-hydroxyquinoline

Melting Point: 102°-104° C.; MS m/z: 216 (M⁺); NMR(DMSO-d₆)δ: 1.16(6H,d), 2.73(3H, s), 4.20(1H, sept), 5.80(1H, d), 6.53(1H, d), 6.88(1H, dd),7.64(1H, dd), 7.84(1H, d), 11.16(1H, brs)

4-Hydroxy-7-morpholinoquinoline

Melting Point: >240° C.; MS m/z: 230 (M⁺); NMR(DMSO-d₆)δ: 3.21-3.34(4H,m), 3.74-3.79(4H, m), 5.87(1H, d), 6.73(1H, d), 7.04(1H, dd), 7.72(1H,t), 7.90(1H, d), 11.33(1H, brs)

4-Hydroxybenzo h!quinoline

Melting Point: 256°-259° C. (dec.) MS m/z: 195 (M⁺); NMR(DMSO-d₆)δ:6.27(1H, d), 7.71-7.77(3H, m), 7.96(1H, dd), 8.04(1H, m), 8.12(1H, d),8.63-8.67(1H, m), 12.15(1H, brs)

4-Hydroxy-7,8,9,10-tetrahydrobenzo h!quinoline

Melting Point: 263°-265° C. (dec.); MS m/z: 199 (M⁺); NMIR(DMSO-d₆)δ:1.73-1.99(4H, m), 2.76-2.85(4H, m), 6.03(1H, d), 7.01(1H, d), 7.74(1H,dd), 7.86(1H, d), 10.89(1H, brs)

7-Benzylthio-4-hydroxyquinoline

Melting Point: 173°-176° C.; MS m/z: 267 (M⁺); NMR(DMSO-d₆)δ: 4.35(2H,s), 5.98(1H, d), 7.22-7.45(7H, m), 7.83(1H, dd), 7.94(1H, d), 11.61(1H,brs)

4-Hydroxy-7-phenoxyquinoline

Melting Point: 176°-179° C.; MS m/z: 237 (M⁺); NMR(DMSO-d₆)δ: 5.96(1H,d), 6.90(1H, d), 6.99(1H, dd), 7.17(2H, d), 7.26(1H, t), 7.48(2H, t),7.80(1H, d), 8.08(1H, d), 11.54(1H, brs)

4-Hydroxy-8-methylquinoline

Melting Point: 209°-210° C. (dec.); MS m/z: 159 (M⁺); NMR(DMSO-d₆)δ:2.48(3H, s), 6.06(1H, d), 7.20(1H, t), 7.47(1H, dd), 7.81(1H, t),7.97(1H, dd), 11.06(1H, brs)

4-Hydroxy-7,8-dimethylquinoline

Melting Point: >300° C.; MS m/z: 173 (M⁺); NMR(DMSO-d₆)δ: 2.37(3H, s),2.38(3H, s), 6.01(1H, d), 7.14(1H, d), 7.79(1H, t), 8.86(1H, d),1O.99(1H, brs)

4-Hydroxy-8-methoxyquinoline

Melting Point: 165°-169° C.; MS m/z: 175 (M⁺); NMR(DMSO-d₆)δ: 3.97(3H,s), 6.03(1H, d), 7.17-7.24(2H, m), 7.63(1H, dd), 7.72(1H, dd), 11.30(1H,brs)

4-Hydroxy-1,7-phenanthroline

Melting Point: 293°-295° C. (dec.); MS m/z: 196 (M⁺); NMR(DMSO-d₆)δ:6.42(1H, brs), 7.74(1H, dd), 7.83(1H,d), 8.10(1H, brs), 8.35(1H, d),9.05(1H, dd), 9.14(1H, dd), 12.26(1H, brs)

4-Hydroxy-,10-phenanthroline

Melting Point: 198°-202° C.; MS m/z: 196 (M⁺); NMR(DMSO-d₆)δ: 6.38(1H,dd), 7.86(1H, d), 7.89(1H, dd), 8.03(1H, dd), 8.25(1H, d), 8.61(1H, dd),9.14(1H, dd), 12.47(1H, brs)

Preparation 2: Preparation of trans-4-hydroxy-7-styrylquinoline

4-Hydroxy-7-iodoquinoline (1.08 g, 4.0 mmol) obtained in the Preparation1, styrene (0.50 g, 4.8 mmol), tri-n-butylamine (0.89 g, 4.8 mmol),palladium acetate (18 mg, 0.08 mmol) and triphenylphosphine (42 mg, 0.16mmol) were reacted in dimethylformamide (DMF; 30 ml) at 120° C. for 2hours. The resulting reactant was added with water (100 ml) and theprecipitates were collected by filtration and dried over calciumchloride. The obtained powder was purified through silica gel columnchromatography (Wako Gel™ C-200, methylene chloride : methanol=9 : 1) toobtain the titled compound (490 mg, 50%).

Melting Point: >250° C. (dec.); MS m/z: 247 (M⁺); NMR(DMSO-d₆)δ:6.02(1H, d), 7.2-7.5(5H, m), 7.6-7.7(4H, m), 7.87(1H, d), 8.07(1H, d),11.74(1H, brs)

Preparation 3: Preparation of 4-hydroxy-7-phenethylquinolinetrans-4-Hydroxy-7-styrylquinoline (280 mg, 1.13 mmol) obtained in thePreparation 2 was dissolved in ethanol (200 ml), hydrogenated in thepresence of 10% palladium on activated carbon (100 mg) and purifiedthrough silica gel column chromatography (Wako Gel™ C-200, methylenechloride : methanol=9 : 1) to obtain the titled compound (220mg, 78%).

Melting Point: 204°-205° C.; FAB-MS m/z: 250 M+H!⁺ ; NMR(DMSO-d₆)δ:2.93-2.99(4H, m), 6.98(1H, d), 7.17-7.30(7H, m), 7.82(1H, dd), 7.98(1H,d), 11.58(1H, brs)

Preparation 4: Preparation of 4-hydroxy-7-dodecylquinoline

Dodecene was used instead of styrene in the Preparation 2 and theprocedure was made in accordance with the Preparation 2 and 3 to obtainthe titled compound.

Melting Point: 90°-91.5° C.; MS m/z: 313 (M⁺); NMR(DMSO-d₆)δ: 0.85(1H,t), 1.23-1.29(18H, m), 1.58-1.64(2H, m), 2.68(2H, t), 5.97(1H, d),7.14(1H, d), 7.28(1H, s), 7.83(1H, d), 7.98(1H, d), 11.59(1H, brs)

Preparation 5: Preparation of4-hydroxy-7-(4-methoxycarbonyl-1-piperazinyl)quinoline

A mixture of 3-(4-methoxycarbonyl-1-piperazinyl)aniline (0.75 g, 3.2mmol), ethyl orthoformate (0.50 g, 3.4 mmol), Meldrum's acid (0.48 g,3.4 mmol) was stirred at 110° C. for 1.5 hours. The reaction mixture wasadded with diphenyl ether (10 ml) and stirred at 240° C. for 1.5 hours.After allowing to cool, n-hexane was added to the mixture. The resultingprecipitates were collected by filtration and purified by columnchromatography (Wako Gel™ C-200, methylene chloride methanol=10 : 1) toobtain the titled compound (320 mg, 35%).

Melting Point:>240° C.; MS m/z: 287 (M⁺); NMR(DMSO-d₆)δ: 3.28(4H, t),3.54(4H, t), 3.64(3H, s), 5.86(1H, d), 6.74(1H, d), 7.03(1H, dd),7.71(1H, dd), 7.90(1H, d), 11.32(1H, brs)

Preparation 6: Preparation of 4-chloro-7-methoxyquinoline

4-Hydroxy-7-methoxy-3-quinolinecarboxylic acid (7.56 g, 4 mmol) obtainedin (2) of the Preparation 2 was added with diphenyl ether (100 ml) anddecarboxylated through heating at 250° C. for 2 hours. After allowing tocool to room temperature, the reactant was added with phosphorusoxychloride (2 ml) and heated at 130° C. for an hour. After allowing tocool, the reactant was poured into ice water (200 ml) and extractedtwice with ethyl acetate (200 ml). The extracted solutions with ethylacetate were combined and washed three times with 2N hydrochloric acid(100 ml). The solution washed with the hydrochloric acid was combinedwith the above-mentioned water layer and adjusted by 2N aqueous solutionof sodium hydroxide to pH 9. The resulting precipitates were collectedby filtration to obtain 5.37 g (80%) of 4-chloro-7-methoxyquinoline.

Melting Point: 86°-88° C.; MS m/z: 193 (M⁺); NMR:δ 3.97(3H, s), 7.29(1H,dd), 7.35(1H, d), 7.43(1H, d), 8.12(1H, d), 8.69(1H, d)

Starting from the various substituted aniline, the procedure was made inaccordance with (1) and (2) of the Preparation 1 to obtain4-hydroxyquinoline-3-carboxylic acid derivatives. Using thesederivatives, the procedure was made in accordance with the Preparation 6to obtain the following 4-haloquinoline derivatives.

4-Chloro-5-methylquinoline

Melting Point: 77-81° C.; MS m/z: 177 (M⁺); NMR:δ 3.05(3H, s), 7.38(1H,dd), 7.45(1H, d), 7.59(1H, dd), 7.98(1H, dd), 8.68(1H, d)

4-Chloro-7-methylquinoline

Melting Point: 28° C.; MS m/z: 177 (M⁺); NMR:δ 2.59(3H, s), 7.43(1H, d),7.48(1H, dd), 7.90(1H, d), 8.12(1H, d), 8.74(1H, d)

4-Chloro-7-nitroquinoline

Melting Point: 171°-173° C.; MS m/z: 208 (M⁺); NMR:δ 7.68(1H, d),8.42(2H, d), 8.96(1H, d), 9.03(1H, t)

7-Carbamoyl-4-chloroquinoline

Melting Point: 241°-242° C. (dec.); MS m/z: 206 (M⁺);

7-Acetyl-4-chloroquinoline

Melting Point: 114°-118° C.; MS m/z: 205 (M⁺); NMR:δ 2.78(3H, s),7.60(1H, d), 8.21(1H, dd), 8.31(1H, d), 8.69(1H, d), 8.88(1H, d)

4-Chloro-7-hydroxymethylquinoline

Melting Point: 138°-139° C.; MS m/z: 193 (M⁺); NMR:δ 4.77(2H, d),5.50(1H, t), 7.70(2H, m), 8.03(1H, s), 8.16(1H, d), 8.82(1H, d)

4-Chloro-7-n-hexylquinoline

MS m/z: 247 (M⁺); NMR:δ 0.88(3H, t), 1.30(6H, m), 1.70(2H, m), 2.84(2H,t), 7.42(1H, d), 7.50(1H, dd), 7.90(1H, d), 8.14(1H, d), 8.74(1H, d)

4-Chloro-7-methoxymethylquinoline

MS m/z: 207 (M⁺); NMR:δ 3.46(3H, s), 4.69(2H, s), 7.48(1H, d), 7.66(1H,d), 8.06(1H, s), 8.23(1H, d), 8.78(1H, d)

4-Chloro-7-methylthioquinoline

Melting Point: 72.5°-73.5° C.; MS m/z: 209 (M⁺); NMR:δ 2.62(3H, s),7.40(1H, d), 7.49(1H, dd), 7.79(1H, d), 8.09(1H, d), 8.71(1H, d)

4-Chloro-7-N,N-dimethylaminoquinoline

Melting Point: 153.0°-154.5° C.; MS m/z: 206 (M⁺); NMR(CDCl₃):δ 3.12(6H,s), 7.15-7.26(3H, m), 8.04(1H,d), 8.59(1H, d)

4-Chloro-7-isopropylthioquinoline

MS m/z: 237 (M⁺); NMR(CDCl₃):δ 1.42(6H, d), 3.68(1H, sept), 7.42(1H,dd), 7.53(1H, dd), 7.98(1H, d), 8.11(1H, d), 8.74(1H, d)

7-Benzyl-4-chloroquinoline

MS m/z: 253 (M⁺); NMR(CDCl₃):δ 4.20(2H, s), 7.20-7.40(5H, m), 7.43(1H,d), 7.48(1H, dd), 7.93(1H, d), 8.13(1H, d), 8.73(1H, d)

7-(2-Naphthyl)-4-chloroquinoline

Melting Point: 119°-121° C.; MS m/z: 289 (M⁺); NMR(CDC1₃):δ 7.48(1H, d),7.52(2H, m), 7.80-8.00(4H, m), 8.04(1H, dd), 8.20(1H, s), 8.31(1H, d),8.46(1H, d), 8.81(1H, d)

Preparation 7: Preparation of 4,7-dichloro-2,3-dihydrofuro2,3-b!quinoline

The titled compound was obtained from 2,4,7-trichloro-3-(β-chloroethyl)quinoline in accordance with an Example shown in Japanese PatentPublication (Kokoku) No. 47-43952.

Melting Point: 98° C.; MS m/z: 239 (M⁺); NMR:δ 3.41(2H, t), 4.76(2H, t),7.36(1H, dd), 7.80(1H, d), 7.91(1H, d)

Preparation 8: Preparation of 4-chloro(bromo)-7-ethoxy-quinoline

(1) 7-Methoxy-4-chloroquinoline(13 g, 67 mmol) was refluxed for 24 hourswith 47% hydrobromic acid (30 ml). After allowing to cool, aqueoussolution of saturated sodium bicarbonate was added for neutralizationand the resulting crystals were filtered. The obtained crystals werewashed with water, sufficiently dried and recrystallized from ethanol toobtain 9 g of 4-chloro(bromo)-7-hydroxyquinoline a mixture of4-chloro-7-hydroxyquinoline and 4-bromo-7-hydroxy-quinoline (7 : 3)!.This mixture was used without further purification as the startingmaterial in a next reaction.

MS m/z: 179 (M⁺, 4-Cl derivative) and 223 (M⁺, 4-Br derivative)

(2) 4-Chloro(bromo)-7-hydroxyquinoline (200 mg) dissolved inN,N-dimethylformamide (DMF; 30 ml) was added with potassium carbonate(203 mg) and ethyl iodide (232 mg) and stirred at room temperature for 8hours. The reaction mixture was added with water (50 ml) and methylenechloride (30 ml) and shaken to separate the organic layer. Further, thewater layer was extracted three times with methylene chloride (30 ml).This extract solution was combined with the above-mentioned organiclayer, washed with saturated saline solution and dried over magnesiumsulfate. This extract solution was detected by thin-layer chromatography(TLC; MERCK, Art. 5554, methylene chloride : methanol=9 : 1) to find UV(254 nm) absorptive spots at Rf values of 0.7 and 0.4. After drying, thesolvent was removed under reduced pressure from the extract solution.The residue was chromatographed by silica gel column chromatography(Wako Gel™ C-200, methylene chloride : methanol=9 : 1). Fractionscorresponding to Rf value of 0.7 were collected and evaporated to obtainthe aimed 4-chloro(bromo)-7-ethoxy-quinoline (185 mg). MS m/z: 207 (M⁺,4-Cl derivative) and 251(M⁺, 4-Br derivative)

Corresponding various halides were reacted, in accordance with theprocedure of (2) in the Preparation 8, with 4-chloro(bromo)-7-hydroxyquinoline to obtain corresponding 4-chloro(bromo)-7-substituted quinolines.

4-Chloro(bromo)-7-isopropoxyquinoline

MS m/z: 221 (M⁺, 4-Cl derivative) and 265(M⁺, 4-Br derivative)

4-Chloro(bromo)-7-n-hexyloxyquinoline

MS m/z: 263 (M⁺, 4-Cl derivative) and 307(M⁺, 4-Br derivative)

7-Benzyloxy-4-chloro(bromo)quinoline

MS m/z: 269 (M⁺, 4-Cl derivative) and 313(M⁺, 4-Br derivative)

4-Chloro(bromo)-7-n-propoxyquinoline

MS m/z: 221 (M⁺, 4-Cl derivative) and 265(M⁺, 4-Br derivative)

4-Chloro(bromo)-7-methanesulfonyloxyquinoline

MS m/z: 257 (M⁺, 4-Cl derivative) and 301(M⁺, 4-Br derivative)

4-Chloro(bromo)-7-dodecyloxyquinoline

MS m/z: 347 (M⁺, 4-Cl derivative) and 391(M⁺, 4-Br derivative)

4-Chloro(bromo)-7-octyloxyquinoline

MS m/z: 291 (M⁺, 4-Cl derivative) and 335(M⁺, 4-Br derivative)

4-Chloro(bromo)-7-(5-ethoxycarbonyl-n-pentyloxy)quinoline

MS m/z: 321 (M⁺, 4-Cl derivative) and 366(M⁺, 4-Br derivative)

Preparation 9: Preparation of 4-hydroxy-8-nitroquinoline

4-Hydroxyquinoline (1.45 g, 10 mmol) was dissolved in 3 ml ofconcentrated sulfuric acid and the solution was cooled -10° C. or less.The solution was gradually added with mixed acid (0.8 ml of concentratednitric acid with 1.2 ml of concentrated sulfuric acid) such that thereaction solution was not elevated in temperature up to 0° C. or more,and stirred at 0° C. for 3 hours. The reaction mixture was poured intocrashed ice and neutralized with 2N aqueous solution of sodiumhydroxide. The resulting precipitates were filtered off and washed withwater. The filtrate was combined with the washing solution and extractedwith methylene chloride. After drying over anhydrous magnesium sulfate,the solvent was removed under reduced pressure. The residue wasdeveloped by silica gel column chromatography (Wako Gel™ C-200,methylene chloride : methanol=20 : 1). Firstly eluted yellow fractionswere collected and the solvent was removed to obtain 380 mg (20%) of4-hydroxy-8-nitroquinoline.

Melting Point: 204°-205.5° C.; MS m/z: 190 (M⁺); NMR:δ 6.24(1H, d),7.51(1H, dd), 7.97(1H, d), 8.56(1H, dd), 8.64(1H, dd), 11.86(1H, brs)

Preparation 10: Preparation of7-(2-benzimidazolyl)-thiomethyl-4-chloroquinoline

(1) Commercially available 4-chloro-7-(trifluoromethyl)-quinoline (8 g,0.035 mol) was added under ice cooling with 30% fuming sulfuric acid (35ml) and stirred at 100° C. for 5 hours. After allowing to cool to roomtemperature, the reactant was poured into ice water and made basicenough with excess concentrated ammonia water, and insoluble materialswere filtered off. The filtrate was adjusted by 2N hydrochloric acid topH 3-4. The resulting jellied precipitate was collected by filtration,washed with ethanol (50 ml) and dried under reduced pressure overphosphorus pentoxide to obtain 5.4 g (74%) of7-carboxy-4-chloroquinoline.

Melting Point: >235° C.; MS m/z: 207 (M⁺);

(2) 7-Carboxy-4-chloroquinoline (5 g, 24.0 mmol) was dissolved in amixed solution of potassium hydroxide (1.49 g, 26.6 mmol) with methanol(150 ml) and stirred at room temperature overnight. The reactant wasevaporated to dryness under reduced pressure. The residue was added withdimethylformamide (DMF; 60 ml) and methyl iodide (3.5 g, 24.6 mmol) inthe order named and stirred at 80° C. for an hour. The reaction mixturewas poured into ice water. The resulting precipitates were collected byfiltration, dried over phosphorus pentoxide and recrystallized fromethanol (20 ml) to obtain 3.6 g (61%) of7-methoxycarbonyl-4-chloroquinoline.

Melting Point: 118°-119° C.; MS m/z: 221 (M⁺); NMR:δ 4.00(3H, s),7.82(1H, d), 8.26(1H, dd), 8.38(1H, d), 8.73(1H, d), 8.95(1H, d)

(3) 7-Methoxycarbonyl-4-chloroquinoline(3.75 g, 0.017 mol) was dissolvedin methanol (200 ml), added under ice-cooling with sodium borohydride(12.9 g, 0.34 mol) and stirred for an hour. The reaction mixture waspoured into ice water. The resulting precipitates were collected byfiltration, dried over phosphorus pentoxide and recrystallized fromchloroform (20 ml) to obtain 1.0 g (30%) of7-hydroxymethyl-4-chloroquinoline.

Melting Point: 138°-139° C.; MS m/z: 193 (M⁺); NMR:δ 4.77(2H, d),5.50(1H, t), 7.70(2H, m), 8.03(1H, s), 8.16(1H, d), 8.82(1H, d)

(4) 7-Hydroxymethyl-4-chloroquinoline (930 mg, 4.82 mmol) dissolved inanhydrous methylene chloride (40 ml) was added with triethylamine (679mg, 6.72 mmol). The mixture was cooled in dry ice/acetone bath, addeddropwise with methanesulfonyl chloride (770 mg, 6.7 mmol) and thereactant was stirred for 20 minutes without the cooling bath. Then, thereactant was added under ice-water cooling with cool aqueous solution ofsaturated sodium bicarbonate (40 ml) and ethyl acetate (150 ml) andshaken to separate the organic layer. The separated organic layer waswashed with saturated saline solution and dried over magnesium sulfate.The solvent was removed to obtain7-methanesulfonylmethyl-4-chloroquinoline as oily product.

MS m/z: 271 (M⁺); NMR: δ3.03(3H, s), 5.46(2H, s), 7.54(1H, d, J=4.6 Hz),7.71(1H, d, J=8.9 Hz), 8.15(1H, s), 8.30(1H, d, J=8.9 Hz), 8.82(1H, d,J=4.6 Hz)

The obtained 7-methanesulfonylmethyl-4-chloroquinoline was dissolved inethanol (70 ml), added under ice-water cooling with2-mercaptobenzimidazole (724 mg, 4.82 mmol), and stirred for 30 minutesat the same temperature, and further stirred for 30 minutes without thecooling bath. The reactant was added with excess water and 2Nhydrochloric acid (40 ml) and washed with ethyl acetate. The water layerwas adjusted by 2N aqueous solution of sodium hydroxide to pH 9-10 andextracted three times with methylene chloride (200 ml). The extractsolution was dried over magnesium sulfate and the solvent was removedunder reduced pressure. The residue was purified by silica gel columnchromatography (Wako Gel™ C-200, methylene chloride : methanol=20 : 1)to obtain 700 mg (45%) of the titled compound.

Melting Point: 165°-167° C. (dec.); MS m/z: 325 (M⁺); NMR:δ 4.82(2H, s),7.12(2H, m), 7.45(2H, br), 7.71(1H, d), 7.86(1H, d), 8.15(1H, s),8.15(1H, d), 8.80(1H, d), 12.60(1H, brs)

Example 1:

7-Methoxyquinoline-4(1H)-thione (compound 1)

4-Hydroxy-7-methoxyquinoline (2.3 g, 13 mmol) dissolved in pyridine (30ml) was added with phosphorus pentasulfide (2.9 g, 13 mmol) and refluxedfor an hour. The reaction mixture was allowed to cool to roomtemperature and the solvent was removed under reduced pressure. Theresidues were added with water (80 ml) and stood at 0° C. for about 30minutes. The resulting precipitates were collected by filtration, washedwith water and recrystallized from mixed solvent (about 60 ml) ofethanol with water (2 : 1) to obtain 1.7 g (68%) of the titled orangecompound.

Melting Point: 196°-201° C.; MS m/z: 191 (M⁺); NMR(DMSO-d₆)δ: 3.89(3H,s), 7.01(1H, d, J=2.3 Hz), 7.10(1H, dd, J=2.3, 9.2 Hz), 7.16(1H, d,J=6.9 Hz), 7.75(1H, dd, J=6.3, 6.9 Hz), 8.60(1H, d, J=9.2 Hz), 12.60(1H,brs)

In accordance with the procedure of the Example 1, the followingcompounds were obtained from corresponding starting materials.

7-Isopropylquinoline-4(1H)-thione (Compound 2)

Melting Point: 167°-176° C. (dec.) MS m/z: 203 (M⁺); NMR(DMSO-d₆)δ:1.27(6H, d, J=6.9 Hz), 3.10(1H, m), 7.24(1H, d, J=6.6 Hz), 7.39(1H, d,J=8.6 Hz), 7.45(1H, s), 7.80(1H, d, J=6.6 Hz), 8.60(1H, d, J=8.6 Hz),12.76(1H, brs)

7-Phenylquinoline-4(1H)-thione (Compound 3)

Melting Point: 166-174° C.; MS m/z: 237 (M⁺); NMR(DMSO-d₆)δ:7.39-7.52(5H, m), 7.62-7.67(4H, m), 8.90(1H, d, J=8.9 Hz)

7-Phenoxymethylquinoline-4(1H)-thione (Compound 6)

Melting Point: 186°-189° C.; MS m/z: 267 (M⁺); NMR(DMSO-d₆)δ: 5.30(2H,s), 6.94-7.35(6H, m), 7.52(1H, d, J=8.6 Hz), 7.71(1H, s), 7.84(1H, t,J=5.6, 6.6 Hz), 8.73(1H, d, J=8.6 Hz), 12.9(1H, brs)

8-Nitroquinoline-4(1H)-thione (Compound 7)

Melting Point: 189°-192° C.; MS m/z: 206 (M⁺); NMR(DMSO-d₆)δ: 7.42(1H,d, J=6.9 Hz), 7.62(1H, dd, J=8.3, 8.3 Hz), 7.85(1H, d, J=6.9 Hz),8.72(1H, dd, J=1.3, 8.3 Hz), 9.11(1H, dd, J=1.3, 8.3 Hz), 12.64(1H, brs)

7-Dodecylquinoline-4(1H)-thione (Compound 30)

Melting Point: 107°-109° C.; MS m/z: 329 (M⁺); NMR(DMSO-d₆)δ: 0.85(3H,t, J=6.6 Hz), 1.23-1.30(18H, m), 1.55-1.68(2H, m), 2.72(2H, t, J=7.6Hz), 7.23(1H, d, J=6.3 Hz), 7.32(1H, d, J=8.6 Hz), 7.41(1H, s), 7.80(1H,t, J=6.3 Hz), 8.58(1H, d, J=8.6 Hz), 12.75(1H, brs)

7-Phenethylquinoline-4(1H)-thione (Compound 31)

Melting Point: 188°-192° C.; FAB-MS m/z: 266 M+H!⁺ ; NMR(DMSO-d₆)δ:2.9-3.1(4H, m), 7.1-7.5(8H, m), 7.78(1H, d, J=6.9 Hz), 8.57(1H, d, J=8.2Hz), 12.76(1H, brs)

trans-7-Styrylquinoline-4(1H)-thione (Compound 32)

Melting Point: 238°-240° C.; FAB-MS m/z: 264 M+H!⁺ ; NMR(DMSO-d₆)δ:7.26(1H, d, J=6.6 ), 7.3-7.8(9H, m), 7.83(1H, d, J=6.6 Hz), 8.65(1H, d,J=8.6 Hz), 12.87(1H, brs)

7-N,N-Dimethylaminomethylquinoline-4(1H)-thione (Compound 33)

Melting Point: 135°-140° C. (dec.); MS m/z: 218 (M⁺); NMR(DMSO-d₆)δ:2.78(6H, s), 4.48(2H, s), 7.32(1H, d, J=5.7 Hz), 7.53(1H, d, J=8.4 Hz),7.83(1H, brd, J=5.7 Hz), 8.30(1H, s), 8.70(1H, d, J=8.4 Hz), 13.55(1H,brs)

7-(N-Isopropyl-N-methylamino)quinoline-4(1H)-thione (Compound 34)

Melting Point: 185°-188° C.; MS m/z: 232 (M⁺); NMR(DMSO-d₆)δ: 1.18(6H,d, J=6.4 Hz), 2.81(3H, s), 4.25(1H, sept, J=6.4 Hz), 6.58(1H, d, J=2.5Hz), 6.95(1H, d, J=6.5 Hz), 7.12(1H, dd, J=2.5, 9.6 Hz), 7.58(1H, t,J=6.5 Hz), 8.44(1H, d, J=9.6 Hz), 12.23(1H, brs)

7-Morpholinoquinoline-4(1H)-thione (Compound 36)

Melting Point: 243°-247° C. (dec.); MS m/z: 246 (M⁺); NMR(DMSO-d₆)δ:3.29(4H, t, J=4.8 Hz), 3.77(4H, t, J=4.8 Hz), 6.78(1H, d, J=2.4 Hz),7.04(1H, dd, J=1.0, 6.5 Hz), 7.26(1H, dd, J=2.4, 9.5 Hz), 7.66(1H, t,J=6.5 Hz), 8.49(1H, d, J=9.5 Hz), 12.41(1H, brs)

7-Benzylthioquinoline-4(1H)-thione (Compound 37)

Melting Point: 171°-175° C.; MS m/z: 283 (M⁺); NMR(DMSO-d₆)δ: 4.32(2H,s), 6.29(1H, d, J=4.6 Hz), 7.21-7.57(7H, m), 7.72(1H, dd, J=1.6, 3.8Hz), 8.21(1H, d, J=8.5 Hz), 13.02(1H, brs)

7-Phenoxyquinoline-4(1H)-thione (Compound 38)

Melting Point: 168°-171° C.; FAB-MS m/z: 254 M+H!⁺ ; NMR(DMSO-d₆)δ:6.98(1H, d, J=2.3 Hz), 7.17-7.23(4H, m), 7.30(1H, t, J=7.4 Hz),7.48-7.55(2H, m), 7.76(1H, brd, J=5.6 Hz), 8.68(1H, d, J=9.2 Hz),12.64(1H, brs)

Benzo h!quinoline-4(1H)-thione (Compound 39)

Melting Point: 223°-227° C. (dec.); MS m/z: 211 (M⁺); NMR(DMSO-d₆)δ:7.51(1H, d, J=6.6 Hz), 7.75-7.89(4H, m), 8.03-8.10(1H, m), 8.72-8.77(2H,m), 13.18(1H, brs)

7,8,9,10-Tetrahydrobenzo h!quinoline-4(1H)-thione (Compound 40)

Melting Point: 212°-214° C. (dec.); MS m/z: 215 (M⁺); NMR(DMSO-d₆)δ:1.76-1.92(4H, m), 2.8-2.9(4H, m), 7.17(1H, d, J=8.6 Hz), 7.28(1H, d,J=6.6 Hz), 7.68(1H, t, J=6.6 Hz), 8.48(1H, d, J=8.6 Hz), 11.95(1H, brs)

8-Methylquinoline-4(1H)-thione (Compound 41)

Melting Point: 223°-227° C.; MS m/z: 175 (M⁺); NMR(DMSO-d₆)δ: 2.55(3H,s), 7.33(1H, d, J=6.6 Hz), 7.35(1H, dd, J=7.3, 8.6 Hz), 7.58(1H, dd,J=1.0, 7.3 Hz), 7.74(1H, d, J=6.6 Hz), 8.58(1H, dd, J=1.0, 8.6 Hz),12.14(1H, brs)

8-Methoxyquinoline-4(1H)-thione (Compound 42)

Melting Point: 195°-199° C.; MS m/z: 191 (M⁺); NMR(DMSO-d₆)δ: 4.03(3H,s), 7.27-7.41(3H, m), 7.66(1H, brs), 8.25(1H, dd, J=1.0, 8.3 Hz),12.47(1H, brs)

1,7-Phenanthroline-4(1H)-thione (Compound 44)

Melting Point: 210°-220° C. (dec.); MS m/z: 212 (M⁺); NMR(DMSO-d₆)δ:7.53(1H, d, J=6.6 Hz), 7.79(1H, dd, J=4.3, 8.6 Hz), 7.92(1H, d, J=6.6Hz), 7.93(1H, d, J=9.6 Hz), 9.00(1H, d, J=9.6 Hz), 9.09(1H, dd, J=1.3,4.3 Hz), 9.17(1H, dd, J=1.3, 8.6 Hz), 13.33(1H, brs)

1,10-Phenanthroline-4(1H)-thione (Compound 45)

Melting Point: 245°-250° C. (dec.); MS m/z: 212 (M⁺); NMR(DMSO-d₆)δ:7.63(1H, dd, J=1.0, 6.6 Hz), 7.94(1H, t, J=6.6 Hz), 7.95(1H, dd, J=4.3,8.3 Hz), 8.00(1H, d, J=8.9 Hz), 8.65(1H, dd, J=1.7, 8.3 Hz), 8.86(1H, d,J=8.9 Hz), 9.18(1H, dd, J=1.7, 4.3 Hz), 13.55(1H, brs)

7,8-Dimethylquinoline-4(1H)-thione (Compound 55)

Melting Point: 204°-209° C.; MS m/z: 189 (M⁺); NMR(DMSO-d₆)δ: 2.41(3H,s), 2.43(3H, s), 7.27(1H, d, J=6.6 Hz), 7.30(1H, d, J=8.9 Hz), 7.72(1H,d, J=6.6 Hz), 8.49(1H, d, J=8.9 Hz)

Example 2:

7-Methoxyquinoline-4(1H)-thione (Compound 1)

4-Chloro-7-methoxyquinoline(965 mg, 5 mmol) and 70% sodium hydrosulfide(800 mg, 10 mmol) were added to ethanol (100 ml) and stirred at roomtemperature for 6 days. Ethanol was removed under reduced pressure fromthe reaction mixture. The residue was chromatographed by silica gelcolumn chromatography, eluted with mixed solution of methylene chloridewith methanol (16 : 1) for collection of yellow bands. The solvent wasremoved and the residue was added with a small amount of methylenechloride. The resulting precipitates were collected by filtration toobtain 590 mg (62%) of the titled compound. This compound was completelythe same as the compound 1 obtained in the Example 1.

In accordance with the procedure of the Example 2, the followingcompounds were obtained from corresponding starting materials.

5-Methylquinoline-4(1H)-thione (Compound 10)

Melting Point: >80° C.; MS m/z: 175 (M⁺); NMR(DMSO-d₆)δ: 3.11(3H, s),7.15(1H, m), 7.27(1H, d, J=6.9 Hz), 7.46-7.54(2H, m), 7.59(1H, d, J=6.9Hz), 12.61(1H, brs)

7-Methylquinoline-4(1H)-thione (Compound 11)

Melting Point: 151°-153° C.; MS m/z: 175 (M⁺); NMR(CD30D)δ: 2.61(3H, s),7.45(1H, dd, J=1.3, 8.6 Hz), 7.50(1H, d, J=1.3 Hz), 7.55(1H, d, J=6.6Hz), 7.82(1H, d, J=6.6 Hz), 8.80(1H, d, J=8.6 Hz)

7-Carbamoylquinoline-4(1H)-thione (Compound 12)

Melting Point: 171°-173° C.; MS m/z: 204 (M⁺); NMR(DMSO-d₆)δ: 7.34(1H,d, J=7 OHz), 7.65(1H, brs), 7.85-7.90(2H, m), 8.13(1H, s), 8.23(1H,brs), 8.68(1H, d, J=8.6 ), 13.00(1H, brs)

7-Acetylquinoline-4(1H)-thione (Compound 13)

Melting Point: 205°-215° C. (dec.); MS m/z: 203 (M⁺); NMR(CD₃ 0D)δ:3.09(3H, s), 7.92(1H, d, J=6.9 Hz), 8.20(1H, d, J=6.9 Hz), 8.38(1H, dd,J=1.7, 8.6 Hz), 8.59(1H, d, J=1.7 Hz), 9.27(1H, d, J=8.6 Hz)

7-Hydroxymethylquinoline-4(1H)-thione (Compound 14)

Melting Point: 180°-185° C.; MS m/z: 191 (M⁺); NMR(DMSO-d₆)δ: 4.66(2H,s), 7.26(1H, d, J=6.6 Hz), 7.35(1H, d, J=8.6 Hz), 7.61(1H, s), 7.80(1H,dd, J=4.0, 6.6 Hz), 8.60(1H, d, J=8.6 Hz), 12.85(1H, brs)

7-n-Hexylquinoline-4(1H)-thione (Compound 15)

Melting Point: 118°-121° C.; MS m/z: 245 (M⁺); NMR(DMSO-d₆)δ: 0.92(3H,t, J=6.9 Hz), 1.35(6H, m), 1.69(2H, m), 2.78(2H, t, J=7.3 Hz), 7.30(1H,d, J=6.3 Hz), 7.39(1H, dd, J=1.3, 8.6 Hz), 7.48(1H, d, J=1.3 Hz),7.86(1H, d, J=6.3 Hz), 8.63(1H, d, J=8.6 Hz), 12.82(1H, brs)

7-Methoxymethylquinoline-4(1H)-thione (Compound 16) MS m/z: 205 (M⁺);NMR(CDCl₃)δ: 3.43(3H, s), 4.55(2H, s), 7.39(1H, dd, J=1.3, 8.6 Hz),7.45(1H, d, J=6.8 Hz), 7.50(1H, d, J=6.8 Hz), 7.62(1H, s), 8.81(1H, d,J=8.6 Hz)

7-Methylthioquinoline-4(1H)-thione (Compound 17)

Melting Point: 191°-194° C.; MS m/z: 207 (M⁺); NMR(DMSO-d₆)δ: 2.58(3H,s), 7.20(1H, d, J=6.6 Hz), 7.33(1H, dd, J=2.0, 8.9 Hz), 7.36(1H, d,J=2.0 Hz), 7.78(1H, m), 8.55(1H, d, J=8.9 Hz), 12.71(1H, brs)

7-Chloro-2,3-dihydrofuro 2,3-b!quinoline-4(1H)-thione (Compound 18)

Melting Point: 284°-286° C.; MS m/z: 237 (M⁺); NMR(DMSO-d₆)δ: 3.23(2H,t, J=8.5 Hz), 3.53(2H, t, J=8.5 Hz), 7.21(1H, dd, J=2.0, 8.5 Hz),7.35(1H, d, J=2.0 Hz), 7.36(1H, d, J=8.5 Hz), 11.68(1H, brs)

7-(2-Naphtyl)quinoline-4(1H)-thione (Compound 46)

Melting Point: 160°-165° C. (dec.); MS m/z: 287 (M⁺); NMR(DMSO-d₆)δ:7.31(1H, d, J=6.0 Hz), 7.57-7.62(2H, m), 7.87-8.10(7H, m), 8.35(1H, s),8.80(1H, d, J=8.6 Hz), 12.91(1H, brs)

7-Benzylquinoline-4(1H)-thione (Compound 47)

Melting Point: 155°-157° C. (dec.); MS m/z: 251 (M⁺); NMR(DMSO-d₆)δ:4.10(2H, s), 7.20-7.36(7H, m), 7.41(1H, s), 7.77(1H, d, J=6.3 Hz),8.60(1H, d, J=8.6 Hz), 12.77(1H, brs)

7-N,N-Dimethylaminoquinoline-4(1H)-thione (Compound 48)

Melting Point: 219.0°-221.0° C.; MS m/z: 204 (M⁺); NMR(DMSO-d₆)δ:3.05(6H, s), 6.52(1H, d, J=2.3 Hz), 6.96(1H, d, J=6.9 Hz), 7.04(1H, dd,J=2.3, 9.2 Hz), 7.59(1H, dd, J=6.3, 6.9 Hz), 8.46(1H, d, J=9.5 Hz),12.27(1H, brs)

7-Isopropylthioquinoline-4(1H)-thione (Compound 49)

Melting Point: 170.0° C. (dec.); MS m/z: 235 (M⁺); NMR(DMSO-d₆)δ:1.35(6H, d, J=6.6 Hz), 3.70(1H, sept, J=6.6 Hz), 7.21(1H, d, J=6.6 Hz),7.37(1H, dd, J=2.0, 8.6 Hz), 7.50(1H, d, J=2.0 Hz), 7.80(1H, t, J=6.3Hz), 8.56(1H, d, J=8.6 Hz), 12.72(1H, brs)

7-(2-Benzimidazolyl)thiomethylquinoline-4(1H)-thione (Compound 50)

Melting Point: >145° C. (dec.); FAB-MS m/z: 324 M+H!⁺ ; NMR(DMSO-d₆)δ:4.77(2H, s), 7.10-7.20(2H, m), 7.25(1H, d, J=6.3 Hz), 7.40(2H, br),7.54(1H, dd, J=1.7, 8.6 Hz), 7.72(1H, d, J=1.7 Hz), 7.78(1H, t, J=6.3Hz), 8.60(1H, d, J=8.6 Hz), 12.60(1H, brs), 12.85(1H, brs)

Example 3:

7-Nitroquinoline-4(1H)-thione (Compound 19)

4-Chloro-7-nitroquinoline (100 mg, 0.48 mmol) and thiourea (100 mg, 1.3mmol) were added to ethanol (50 ml) and stirred at 80° C. for 30minutes. After allowing to cool to room temperature, ethanol was removedunder reduced pressure. The residue was chromatographed by silica gelcolumn chromatography and eluted with mixed solution of methylenechloride with methanol (19 : 1) for collection of yellow bands. Thesolvent was removed to obtain 7 mg (7%) of the titled yellow compound.

Melting Point: >250° C.; MS m/z: 206 (M⁺); NMR(CD₃ 0D)δ: 7.45(1H, d,J=6.9 Hz), 7.73(1H, d, J=6.9 Hz), 8.08(1H, dd, J=2.3, 9.2 Hz), 8.39(1H,d, J=2.3 Hz), 8.87(1H, d, J=9.2 Hz)

Example 4:

7-Ethoxyquinoline-4(1H)-thione (Compound 22)

4-Chloro(bromo)-7-ethoxyquinoline (180 mg) and 70% sodium hydrosulfide(250 mg) were dissolved in methanol(50 ml) and refluxed for 15 hours.This reaction mixture was evaporated under reduced pressure and theresidue was developed by silica gel column chromatography Wako Gel™C-200, mixed solution of methylene chloride with methanol (9 : 1)!.Fractions corresponding to yellow spots were collected and evaporated toobtain crude crystals. The obtained crude crystals were recrystallizedfrom 40% aqueous ethanol solution to obtain 107 mg of the titledcompound. Melting Point: 171°-174° C.; MS m/z: 205 (M⁺); NMR(DMSO-d₆)δ:1.40(3H, t, J=6.9 Hz), 4.15(2H, q, J=6.9 Hz), 7.02(1H, d, J=1.3 Hz),7.09(1H, dd, J=2.3, 9.2 Hz), 7.15(1H, d, J=6.5 Hz), 7.73-7.78(1H, m),8.58(1H, d, J=9.2 Hz), 12.68(1H, brs)

In accordance with the procedure of the Example 4, the followingcompounds were obtained from corresponding starting materials.

7-Isopropyloxyquinoline-4(1H)-thione (Compound 23)

Melting Point: 174°-176° C.; MS m/z: 219 (M⁺); NMR(DMSO-d₆)δ: 1.42(6H,d, J=5.9 Hz), 4.80(1H, sept, J=5.9 Hz), 7.08(1H, d, J=2.3 Hz), 7.15(1H,dd, J=2.3, 9.2 Hz), 7.21(1H, d, J=6.3 Hz), 7.83(1H, dd, J=6.3, 6.6 Hz),8.64(1H, d, J=9.2 Hz), 12.67(1H, brs)

7-n-Hexyloxyquinoline-4(1H)-thione (Compound 24)

Melting Point: 153°-156° C.; MS m/z: 261 (M⁺); NMR(DMSO-d₆)δ: 0.91(3H,t, J=6.6 Hz), 1.31-1.49(6H, m), 1.80(2H, quint, J=6.6 Hz), 4.10(2H, t,J=6.6 Hz), 7.02(1H, d, J=2.3 Hz), 7.10(1H, dd, J=2.3, 9.2 Hz), 7.16(1H,d, J=6.3 Hz), 7.77(1H, dd, J=6.3, 6.6 Hz), 8.59(1H, d, J=9.2 Hz),12.63(1H, brs)

7-Benzyloxyquinoline-4(1H)-thione (Compound 25)

Melting Point: 166°-170° C.; MS m/z: 267 (M⁺); NMR(DMSO-d₆)δ: 5.33(2H,s), 7.18-7.28(3H, m), 7.41-7.60(5H, m), 7.84(1H, dd, J=5.9, 6.6 Hz),8.68(1H, d, J=9.2 Hz), 12.76(1H, brs)

7-n-Propoxyquinoline-4(1H)-thione (Compound 26)

Melting Point: 178°-182° C.; MS m/z: 219 (M⁺); NMR(DMSO-d₆)δ: 1.10(3H,t, J=7.3 Hz), 1.92(2H, sext, J=7.3 Hz), 4.13(2H, t, J=6.6 Hz), 7.09(1H,d, J=2.3 Hz), 7.18(1H, dd, J=2.3, 9.2 Hz), 7.23(1H, d, J=2.3 Hz),7.80(1H, dd, J=6.3, 6.6 Hz), 8.66(1H, d, J=9.2 Hz), 12.71(1H, brs)

7-Hydroxyquinoline-4(1H)-thione (Compound 27)

Melting Point: 245°-255° C. (dec.); MS m/z: 177 (M⁺); NMR(DMSO-d₆)δ:6.99(1H, d, J=2.0 Hz), 7.04(1H, dd, J=2.3, 9.2 Hz), 7.17(1H, d, J=6.6Hz), 7.78(1H, d, J=6.6 Hz), 8.61(1H, d, J=9.2 Hz), 10.64(1H, s),12.63(1H, brs)

7-Methanesulfonyloxyquinoline-4(1H)-thione (Compound 28)

Melting Point: 185°-188° C.; MS m/z: 255 (M⁺); NMR(DMSO-d₆)δ: 3.59(3H,s), 7.39(1H, d, J=6.6 Hz), 7.52(1H, dd, J=2.3, 9.2 Hz), 7.73(1H, d,J=2.3 Hz), 7.99(1H, dd, J=6.6, 6.3 Hz), 8.83(1H, d, J=9.2 Hz), 13.05(1H,brs)

7-Dodecyloxyquinoline-4(1H)-thione (Compound 52)

Melting Point: 141°-145° C.; MS m/z: 345 (M⁺); NMR(DMSO-d₆)δ: 0.85(3H,t, J=6.6 Hz), 1.24-1.44(18H, m), 1.72-1.82(2H, m), 4.08(2H, t, J=6.6HZ), 6.99(1H, d, J=2.3 Hz), 7.07(1H, dd, J=2.3, 9.2 Hz), 7.14(1H, d,J=6.6 Hz), 7.75(1H, t, J=6.6 Hz), 8.58(1H, d, J=9.2 Hz), 12.60(1H, brs)

7-Octyloxyquinoline-4(1H)-thione (Compound 53)

Melting Point: 150°-154° C.; MS m/z: 289 (M⁺); NMR(DMSO-d₆)δ: 0.87(3H,t, J=6.6 Hz), 1.27-1.44(1OH, m), 1.73-1.83(2H, m), 4.08(2H, t, J=6.6Hz), 7.00(1H, d, J=2.3 Hz), 7.07(1H, dd, J=2.3, 9.2 Hz), 7.15(1H, d,J=6.6 Hz), 7.75(1H, t, J=6.6 Hz), 8.58(1H, d, J=9.2 Hz), 12.60(1H, brs)

7-(5-Carboxy-n-pentyloxy)quinoline-4(1H)-thione (Compound 51)

Melting Point: 186°-190° C.; FAB-MS m/z: 292 M+H!⁺ ; NMR(DMSO-d₆)δ:1.40-1.85(6H, m), 2.25(2H, t, J=6.9 Hz), 4.08(2H, t, J=6.6 Hz), 7.00(1H,d, J=2.3 Hz), 7.06(1H, dd, J=2.3, 9.2 Hz), 7.15(1H, d, J=6.6 Hz),7.74(1H, m), 8.58(1H, d, J=9.2 Hz), 11.98(1H, brs), 12.61(1H, brs)

Example 5:

7-Acetoxymethylquinoline-4(1H)-thione (Compound 29)

7-Hydroxymethylquinoline-4(1H)-thione(60 mg, 0.3 mmol) obtained in theExample 2 was dissolved in acetic anhydride (5 ml). The mixture wasadded with pyridine (23.5 mg, 0.3 mmol) and stirred at room temperaturefor 24 hours. Excess water was added under cooling to the reactionmixture for decomposition of acetic anhydride into homogeneous solution.Then, the solution was adjusted by 2N aqueous solution of sodiumhydroxide to pH 5.5 and the resulting precipitates were filtered off.The filtrate was further adjusted by saturated aqueous solution ofpotassium carbonate to pH 8-9. Then, the filtrate was extracted withethyl acetate (20 ml×3), and the combined extract solutions were washedwith water and dried over magnesium sulfate. The solvent was removedunder reduced pressure and the residue was sufficiently washed withether to obtain 34 mg (46%) of the titled orange compound.

Melting Point: 153°-156° C.; MS m/z: 233 (M⁺); NMR(DMSO-d₆)δ: 2.13(3H,s), 5.24(2H, s), 7.28(1H, d, J=6.6 Hz), 7.43(1H, dd, J=1.3, 8.6 Hz),7.62(1H, s), 7.83(1H, m), 8.65(1H, d, J=8.6 Hz), 12.89(1H, brs)

Example 6:

7-(1-Piperazinyl)quinoline-4(1H)-thione (Compound 54)

4-Hydroxy-7-(4-methoxycarbonyl-1-piperazinyl)quinoline (0.32 g, 1.1mmol) dissolved in methanol (5 ml) was added with 2N sodium hydroxide(1.6 ml) and stirred with heating for 12 hours. After allowing to cool,methanol was removed under reduced pressure. The residue was added withwater (10 ml) and adjusted by 5% hydrochloric acid to pH 7 and the waterwas removed under reduced pressure. This residue was siispended inpyridine (5 ml), added with phosphorus pentasulfide (0.25 g, 1.1 mmol)and stirred at 100° C. for 1.5 hours. After allowing to cool, pyridinewas removed under reduced pressure and the residue was purified bypreparative TLC (Merck Art. 13895, methylene chloride : methanol :ammonia water=50 : 10 : 1) to obtain 21 mg (8%) of the titled compound.

Melting Point: 220°-225° C. (dec.); MS m/z: 245 (M⁺); NMR(DMSO-d₆)δ:3.24(4H, brs), 3.56(4H, brs), 6.94(1H, brs), 7.07(1H, d, J=6.4 Hz),7.27(1H, d, J=9.4 Hz), 7.67(1H, d, J=6.4 Hz), 8.51(1H, d, J=9.4 Hz),9.30(1H, brs)

Example 7:

Sodium salt of 7-(5-carboxy-n-pentyloxy)quinoline-4(1H)-thione

7-(5-Carboxy-n-pentyloxy)quinoline-4(1H)-thione (43.7 mg, 0.15 mmol) andsodium carbonate (7.9 mg, 0.075 mmol) were stirred in water (50 ml)overnight and freeze-dried to obtain 43.2 mg (92%) of the titledcompound.

Melting Point: 231°-235° C.; NMR(DMSO-d₆)δ: 1.4-1.8(6H, m), 2.09(2H, t,J=6.9 Hz), 4.01(2H, t, J=6.6 Hz), 6.87(1H, dd, J=2.3, 9.3 Hz), 7.03(1H,d, J=2.3 Hz), 7.33(1H, d, J=5.3 Hz), 7.80(1H, d, J=5.3 Hz), 8.59(1H, d,J=9.2 Hz)

Capability Of Exploitation In Industry

The compound according to the present invention has excellent selectiveantibacterial activity against Helicobacter pylori and therefore iseffective for treatment and prevention of reccurrence of peptic ulcersand chronic gastritis with Helicobacter pylori infections.

We claim:
 1. A thioquinolone compound represented by the formula I orpharmaceutically acceptable salt thereof: ##STR5## wherein R₁ and R₂respectively represent hydrogen atom or R₁ and R₂ are joined to form--O--(CH₂)₂ --;R₃ represents halogen atom, C₁ -C₁₂ alkyl group, C₁ -C₁₂alkoxy group, lower alkylsulfonyloxy group, carboxy lower alkoxy group,lower alkylthio group, benzyloxy group, benzylthio group, phenoxy group,styryl group, nitro group, phenyl group, naphthyl group, piperazinylgroup, morpholino group or hydroxyl group or represents --CH₂ R₅, --COR₆or --NR₇ R₈ wherein R₅ represents benzyl group, phenyl group, hydroxylgroup, lower alkoxy group, lower alkylcarbonyloxy group, phenoxy group,di-lower alkylamino group or benzimidazolylthio group, R₆ representslower alkyl group or amino group and R₇ and R₈ respectively representlower alkyl group; and R₄ represents hydrogen atom or lower alkyl groupor is coupled with R₃ to form cyclohexene ring, benzene ring or pyridinering, R₃ being not halogen atom at any of positions 5 to 8, methyl groupat position 6 or methoxy group at position 6 of the quiinoline ring whenR₁, R₂ and R₄ are respectively hydrogen atom, R₃ and R₄ being not atpositions 6 and 7 or positions 6 and 8 of the quinoline ring when R₁ andR₂ are respectively hydrogen atom and R₄ is lower alkyl group.
 2. Thecompound according to claim 1 wherein R₁, R₂ and R₄ are respectivelyhydrogen atom.
 3. The compound according to claim 1 wherein R₁, R₂ andR₄ are respectively hydrogen atom and R₃ is at position 7 of thequinoline ring.
 4. The compound according to claim 3 wherein R₃ is C₁-C₁₂ alkyl group, C₁ -C₁₂ alkoxy group, benzyl group, phenethyl group,lower alkoxymethyl group, lower alkylcarbonyloxymethyl group,phenoxymethyl group, styryl group, phenyl group, phenoxy group,carboxy-lower alkoxy group, lower alkylsulfonyloxy group, loweralkylthio group, benzylthio group, di-lower alkylamino group,piperazinyl group, morpholino group or benzimidazolylthiomethyl group.5. The compound according to claim 1 wherein R₁, R₂ and R₄ arerespectively hydrogen atom and R₃ is at position 8 of the quinolinering.
 6. The compound according to claim 5 wherein R₃ is lower alkylgroup or lower alkoxy group.
 7. The compound according to claim 1wherein R₁ and R₂ are respectively hydrogen atom and R₃ and R₄ are atpositions 7 and 8 of the quinoline ring.
 8. The compound according toclaim 7 wherein R₃ and R₄ are respectively lower alkyl group.
 9. Thecompound according to claim 7 wherein R₃ and R₄ are joined to formcyclohexene ring or benzene ring.
 10. A pharmaceutical compositioncontaining an effective amount of compound according to any one ofclaims 1 to 9 and a pharmaceutically acceptable diluent or carrier. 11.The compound according to claim 1, wherein R₃ represents halogen atom,C₁ -C₁₂ alkyl group, C₁ -C₁₂ alkoxy group, lower alkylsulfonyloxy group,carboxy lower alkoxy group, lower alkylthio group, benzyloxy group,benzylthio group, phenoxy group, styryl group, nitro group, phenylgroup, naphthyl group, morpholino group or hydroxyl group or represents--CH₂ R₅, --COR₆ or --NR₇ R₈ wherein R₅ represents benzyl group, phenylgroup, hydroxyl group, lower alkoxy group, lower alkylcarbonyloxy group,phenoxy group, di-lower alkylamino group or benzimidazolylthio group, R₆represents lower alkyl group or amino group and R₇ and R₈ respectivelyrepresent lower alkyl group.
 12. An antibacterial agent effectiveagainst Helicobacter, wherein the agent comprises the compound accordingto claim
 1. 13. The antibacterial agent according to claim 12, whereinthe agent is effective against Helicobacter pylori.
 14. A method ofinhibiting the growth of cells of Helicobacter comprising the step ofcontacting the cells with an effective amount of a thioquinolonecompound represented by the formula I or pharmaceutically acceptablesalt thereof: ##STR6## wherein R₁ and R₂ respectively represent hydrogenatom or R₁ and R₂ are joined to form --O--(CH₂)₂ --;R₃ representshalogen atom, C₁ -C,₂ alkyl group, C₁ -C₁₂ alkoxy group, loweralkylsulfonyloxy group, carboxy lower alkoxy group, lower alkylthiogroup, benzyloxy group, benzylthio group, phenoxy group, styryl group,nitro group, phenyl group, naphthyl group, piperazinyl group, morpholinogroup or hydroxyl group or represents --CH₂ R₅, --COR₆ or --NR₇ R,wherein R₅ represents benzyl group, phenyl group, hydroxyl group, loweralkoxy group, lower alkylcarbonyloxy group, phenoxy group, di-loweralkylamino group or benzimidazolylthio group, R₆ represents lower alkylgroup or amino group and R₇ and R₈ respectively represent lower alkylgroup; and R₄ represents hydrogen atom or lower alkyl group or iscoupled with R₃ to form cyclohexene ring, benzene ring or pyridine ring,R₃ being not halogen atom at any of positions 5 to 8, methyl group atposition 6 or methoxy group at position 6 of the quinoline ring when R₁,R₂ and R₄ are respectively hydrogen atom, R₃ and R₄ being not atpositions 6 and 7 or positions 6 and 8 of the quinoline ring when R₁ andR₂ are respectively hydrogen atom and R₄ is lower alkyl group.
 15. Themethod according to claim 14, wherein the cells are cells ofHelicobacter pylori.
 16. A method of treating peptic ulcer or chronicgastritis comprising the step of administering to a patient in needthereof an effective amount of a thioquinolone compound represented bythe formula I or pharmaceutically acceptable salt thereof: ##STR7##wherein R₁ and R₂ respectively represent hydrogen atom or R.sub. and R₂are joined to form --O--(CH₂)₂ --;R₃ represent halogen atom, C₁ -C₁₂alkyl group, C₁ -C₁₂ alkoxy group, lower alkylsulfonyloxy group, carboxylower alkoxy group, lower alkylthio group, benzyloxy group, benzylthiogroup, phenoxy group, styryl group, nitro group, phenyl group, naphthylgroup, piperazinyl group, morpholino group or hydroxyl group orrepresents --CH₂ R₅, --COR₆ or --NR₇ R₅ wherein R₅ represents benzylgroup, phenyl group, hydroxyl group, lower alkoxy group, loweralkylcarbonyloxy group, phenoxy group, di-lower alkylamino group orbenzimidazolylthio group, R₆ represents lower alkyl group or amino groupand R₇ and R₈ respectively represent lower alkyl group; and R₄represents hydrogen atom or lower alkyl group or is coupled with R₃ toform cyclohexene ring, benzene ring or pyridine ring, R₃ being nothalogen atom at any of positions 5 to 8, methyl group at position 6 ormethoxy group at position 6 of the quinoline ring when R₁, R₂ and R₄ arerespectively hydrogen atom, R₃ and R₄ being not at positions 6 and 7 orpositions 6 and 8 of the quinoline ring when R₁ and R₂ are respectivelyhydrogen atom and R₄ is lower alkyl group.
 17. The method according toclaim 16, wherein the compound is administered orally or parenterally.18. The method according to claim 17, wherein, if the compound isadministered orally, the compound is administered in the form of atablet, powder, granule, capsule, microcapsule, or syrup.
 19. The methodaccording to claim 17, wherein, if the compound is administeredparenterally, the compound is administered in the form of an injection.20. The method according to claim 19, wherein the compound is infreeze-dried form or in the form of a suppository.